Carbazole derivatives acting on 5-ht7 receptor

ABSTRACT

Disclosed are carbazole derivatives and pharmaceutically acceptable salts thereof that act on the 5-HT 7  receptor. The carbazole derivatives and the pharmaceutically acceptable salts thereof have high binding affinities for the 5-HT 7  serotonin receptor and antagonistic activities against the 5-HT 7  serotonin receptor. Further disclosed are pharmaceutical compositions including the compounds as active ingredients. The pharmaceutical compositions are useful as therapeutic and prophylactic agents for central nervous system diseases where antagonistic activities against 5-HT 7  are required, such as depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, body temperature dysregulation, circadian rhythm dysregulation, sleep disturbance, and smooth muscle-related diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119 to Korean PatentApplication No. 10-2014-0048074 filed on Apr. 22, 2014 in the KoreanIntellectual Property Office, the disclosure of which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to carbazole derivatives andpharmaceutically acceptable salts thereof that act on the 5-HT₇receptor, methods for preparing the compounds, and pharmaceuticalcompositions containing the compounds as active ingredients.

2. Description of the Related Art

The neurotransmitter serotonin acts on 14 different serotonin receptorsdistributed in various organs and is responsible for variousphysiological phenomena. Of these, the 5-HT₇ subtype is the mostrecently cloned serotonin receptor and is known to be abundantlydistributed, particularly in the hypothalamus, thalamus, hippocampus,and cortex. The 5-HT₇ receptor is also found in peripheral tissues, suchas spleen, stomach, intestine, and coronary artery, as well as in thebrain tissues. Such expression patterns indicate that the 5-HT₇ receptoris involved in various functions and pathologies. Particularly, the5-HT₇ receptor is known to perform important functions inthermoregulation, circadian rhythm, learning and memory, sleep, andhippocampal signal transduction (Lowenberg, T. N. et al., Neuron (1993)11: 449-458). The 5-HT₇ receptor is also known to be implicated inneurological diseases, such as depression, migraine, anxiety, and pain,particularly inflammatory pain and neuropathic pain (see a) Schoeffter,P. et al. Br J Pharmacol (1996) 117: 993-994; b) Terron, J. A., Eur. J.Pharmacol (2002) 439: 1-11).

Numerous efforts have been made so far to develop 5-HT₇ receptorantagonists and agonists. However, only a few selective 5-HT₇ receptorantagonists were reported. For example, International Patent PublicationNos. WO 97/48681, WO 97/29097, WO 97/49695, WO 00/56712, and WO 03/48118disclose sulfonamide-based antagonists. Further, International PatentPublication Nos. WO 99/24022 and WO 00/000472 disclosetetrahydroisoquinoline derivatives acting on the 5-HT₇ receptor.

Despite the research, a need still exists to find compounds that haveselective pharmacological activities against the 5-HT₇ receptor,achieving excellent pharmacological effects against 5-HT₇receptor-mediated diseases and conditions and good pharmaceuticalproperties in terms of administration, dispersion, uptake, distribution,metabolism, and excretion.

SUMMARY OF THE INVENTION

It is a first object of the present invention to provide carbazolederivatives and pharmaceutically acceptable salts thereof that act onthe 5-HT₇ receptor.

It is a second object of the present invention to provide methods forpreparing the carbazole derivatives.

It is a third object of the present invention to provide pharmaceuticalcompositions which include the carbazole derivatives and thepharmaceutically acceptable salts thereof as active ingredients and arethus effective in treating or preventing central nervous systemdiseases, such as depression, migraine, anxiety, pain, inflammatorypain, neuropathic pain, body temperature dysregulation, circadian rhythmdysregulation, sleep disturbance, and smooth muscle-related diseases.

One aspect of the present invention provides a carbazole derivativerepresented by Formula 1:

wherein X is CH₂ or C(O), Y is selected from NR₁R₂, piperidinyl groupssubstituted with R₃ and R₄, piperazinyl groups in which the nitrogenatom is substituted with R₅, and morpholinyl groups, n is an integerfrom 2 to 5, R₁ and R₂, which may be identical or different, are eachindependently selected from C₁-C₆ alkyl, phenyl, and benzyl, with theproviso that R₁ and R₂ may be bonded together to form a ring, R₃ and R₄,which may be identical or different, are each independently selectedfrom hydrogen, C₁-C₆ alkyl, phenyl, and benzyl, and R₅ is selected fromC₁-C₆ alkyl, C₁-C₄ alkylcarbonyl, phenyl substituted with C₁-C₄alkyloxy, hydroxyphenyl, benzyl, and benzoisoxazol-3-yl, or apharmaceutically acceptable salt thereof; and

a pharmaceutical composition including the carbazole derivative orpharmaceutically acceptable salt thereof as an active ingredient.

A further aspect of the present invention provides a method forpreparing the carbazole derivative represented by Formula 1, includingalkylating or acylating carbazole to prepare a carbazole intermediateand reacting the carbazole intermediate with a secondary amine compound.

Another aspect of the present invention provides a pharmaceuticalcomposition for preventing and treating a central nervous systemdisease, including the carbazole derivative represented by Formula 1 orpharmaceutically acceptable salt thereof as an active ingredient.

The central nervous system disease may be selected from the groupconsisting of depression, migraine, anxiety, pain, inflammatory pain,neuropathic pain, body temperature dysregulation, circadian rhythmdysregulation, sleep disturbance, smooth muscle-related diseases, andcombinations thereof.

The carbazole derivative and the pharmaceutically acceptable saltthereof according to the present invention exhibit high bindingaffinities for and antagonistic activities against the 5-HT₇ serotoninreceptor. Therefore, the pharmaceutical composition of the presentinvention, which includes the carbazole derivative or pharmaceuticallyacceptable salt thereof as an active ingredient, is effective intreating and preventing central nervous system diseases whereantagonistic activities against 5-HT₇ are required, such as depression,migraine, anxiety, pain, inflammatory pain, neuropathic pain, bodytemperature dysregulation, circadian rhythm dysregulation, sleepdisturbance, and smooth muscle-related diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

These and/or other aspects and advantages of the invention will becomeapparent and more readily appreciated from the following description ofthe embodiments, taken in conjunction with the accompanying drawings ofwhich:

FIG. 1 shows the preventive effect of a compound prepared in Example2.10 on migraine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in more detail.

In one aspect, the present invention provides a carbazole derivativerepresented by Formula 1:

wherein X is CH₂ or C(O), Y is selected from NR₁R₂, piperidinyl groupsin which two of the carbon atoms are substituted with R₃ and R₄,piperazinyl groups in which the nitrogen atom is substituted with R₅,and morpholinyl groups, n is an integer from 2 to 5, R₁ and R₂, whichmay be identical or different, are each independently selected fromC₁-C₆ alkyl, phenyl, and benzyl, with the proviso that R₁ and R₂ may bebonded together to form a ring, R₃ and R₄, which may be identical ordifferent, are each independently selected from hydrogen, C₁-C₆ alkyl,phenyl, and benzyl, and R₅ is selected from C₁-C₆ alkyl, C₁-C₄alkylcarbonyl, phenyl substituted with C₁-C₄ alkyloxy, hydroxyphenyl,benzyl, and benzoisoxazol-3-yl; or a pharmaceutically acceptable saltthereof.

When Y in Formula 1 is NR₁R₂, R₁ and R₂ may be bonded together to form aring. In this case, Y may be, for example, a heterocyclic group selectedfrom the group consisting of pyrrolidinyl, piperidinyl, and azepanyl.The heterocyclic group may be substituted with C₁-C₅ alkyl.

In the present invention, Y in Formula 1 may be particularly selectedfrom, but not limited to, methylbutylaminyl, methylbenzylaminyl,pyrrolidinyl, azepanyl, morpholinyl, 4-methylpiperidinyl,3-methylpiperidinyl, 3,5-dimethylpiperidinyl, 4-phenylpiperidinyl,4-benzylpiperidinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl,4-(2-methoxyphenyl)piperazinyl, 4-(2-hydroxyphenyl)piperazinyl,4-benzylpiperazinyl, and 4-(benzoisoxazol-3-yl)piperazinyl.

In the present invention, the C₁-C₆ alkyl may be linear or branchedalkyl. Specifically, the C₁-C₆ alkyl may be selected from methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, and isohexyl.

In the present invention, the C₁-C₄ alkylcarbonyl may be selected fromacetyl, propionyl, and butanon-1-yl.

In the present invention, the phenyl substituted with C₁-C₄ alkyloxy maybe selected from the group consisting of methoxyphenyl, ethoxyphenyl,propoxyphenyl, dimethoxyphenyl, diethoxyphenyl, and trimethoxyphenyl.

In the present invention, the pharmaceutically acceptable salt may beprepared using any suitable acid commonly used in the art. Specificexamples of such acids include, but are not particularly limited to:non-toxic inorganic acids, such as hydrochloric acid, hydrobromic acid,sulfonic acid, amidosulfuric acid, phosphoric acid, and nitric acid; andnon-toxic organic acids, such as acetic acid, propionic acid, succinicacid, glycolic acid, stearic acid, lactic acid, tartaric acid, citricacid, para-toluenesulfonic acid, and methanesulfonic acid.

In the present invention, the carbazole derivative represented byFormula 1 may be selected from compounds represented by Formulae 2 to 5:

wherein X, n, R₁, and R₂ are as defined in Formula 1;

wherein X, n, R₂, and R₃ are as defined in Formula 1;

wherein X, n, and R₅ are as defined in Formula 1; and

wherein X and n are as defined in Formula 1.

In Formula 2, the dashed line between R₁ and R₂ indicates that R₁ and R₂may be optionally linked together to form a condensed ring.

In the present invention, the carbazole derivative represented byFormula 1 is particularly preferably selected from the followingCompounds 1 to 60:

Compound 1: 6-(Butyl(methyl)amino)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 2: 6-(Benzyl(methyl)amino)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 3: 1-(9H-carbazol-9-yl)-6-(pyrrolidin-1-yl)hexan-1-one

Compound 4: 1-(9H-carbazol-9-yl)-6-(4-methylpiperidin-1-yl)hexan-1-one

Compound 5: 1-(9H-carbazol-9-yl)-6-(3-methylpiperidin-1-yl)hexan-1-one

Compound 6:1-(9H-carbazol-9-yl)-6-(3,5-dimethylpiperidin-1-yl)hexan-1-one

Compound 7: 6-(Azepan-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 8: 1-(9H-carbazol-9-yl)-6-morpholinohexan-1-one

Compound 9: 1-(9H-carbazol-9-yl)-6-(4-phenylpiperidin-1-yl)hexan-1-one

Compound 10: 6-(4-Benzylpiperidin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 11: 6-(4-Acetylpiperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 12: 1-(9H-carbazol-9-yl)-6-(4-methylpiperazin-1-yl)hexan-1-one

Compound 13: 6-(4-Benzylpiperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 14:6-(4-Benzo[d]isoxazol-3-yl)piperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one

Compound 15:1-(9H-carbazol-9-yl)-6-(4-(2-hydroxyphenyl)piperazin-1-yl)hexan-1-one

Compound 16:1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one

Compound 17: 5-(Butyl(methyl)amino)-1-(9H-carbazol-9-yl)pentan-1-one

Compound 18: 5-(Benzyl(methyl)amino)-1-(9H-carbazol-9-yl)pentan-1-one

Compound 19: 1-(9H-carbazol-9-yl)-5-(pyrrolidin-1-yl)pentan-1-one

Compound 20: 1-(9H-carbazol-9-yl)-5-(4-methylpiperidin-1-yl)pentan-1-one

Compound 21: 1-(9H-carbazol-9-yl)-5-(3-methylpiperidin-1-yl)pentan-1-one

Compound 22:1-(9H-carbazol-9-yl)-5-(3,5-dimethylpiperidin-1-yl)pentan-1-one

Compound 23: 5-(Azepan-1-yl)-1-(9H-carbazol-9-yl)pentan-1-one

Compound 24: 1-(9H-carbazol-9-yl)-5-morpholinopentan-1-one

Compound 25: 1-(9H-carbazol-9-yl)-5-(4-phenylpiperidin-1-yl)pentan-1-one

Compound 26: 5-(4-Benzylpiperidin-1-yl)-1-(9H-carbazol-9-yl)pentan-1-one

Compound 27: 5-(4-Acetylpiperazin-1-yl)-1-(9H-carbazol-9-yl)pentan-1-one

Compound 28: 1-(9H-carbazol-9-yl)-5-(4-methylpiperazin-1-yl)pentan-1-one

Compound 29: 5-(4-Benzylpiperazinyl)-1-(9H-carbazol-9-yl)pentan-1-one

Compound 30:1-(9H-carbazol-9-yl)-5-(4-(2-hydroxyphenyl)piperazin-1-yl)pentan-1-one

Compound 31:1-(9H-carbazol-9-yl)-5-(4-(2-methoxyphenyl)piperazin-1-yl)pentan-1-one

Compound 32: 4-(4-Benzylpiperazin-1-yl)-1-(9H-carbazol-9-yl)butan-1-one

Compound 33:1-(9H-carbazol-9-yl)-4-(4-(2-hydroxyphenyl)piperazin-1-yl)butan-1-one

Compound 34:1-(9H-carbazol-9-yl)-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-1-one

Compound 35: N-butyl-6-(9H-carbazol-9-yl)-N-methylhexane-1-amine

Compound 36: N-benzyl-6-(9H-carbazol-9-yl)-N-methylhexane-1-amine

Compound 37: 9-(6-(Pyrrolidin-1-yl)hexyl)-9H-carbazole

Compound 38: 9-(6-(4-Methylpiperidin-1-yl)hexyl)-9H-carbazole

Compound 39: 9-(6-(3-Methylpiperidin-1-yl)hexyl)-9H-carbazole

Compound 40: 9-(6-(3,5-Dimethylpiperidin-1-yl)hexyl)-9H-carbazole

Compound 41: 9-(6-(Azepan-1-yl)hexyl)-9H-carbazole

Compound 42: 4-(6-(9H-carbazol-9-yl)hexyl)morpholine

Compound 43: 9-(6-(4-Phenylpiperidin-1-yl)hexyl)-9H-carbazole

Compound 44: 9-(6-(4-Benzylpiperidin-1-yl)hexyl)-9H-carbazole

Compound 45: 1-(4-(6-(9H-carbazol-9-yl)hexyl)piperazin-1-yl)ethanone

Compound 46: 9-(6-(4-Methylpiperazin-1-yl)hexyl)-9H-carbazole

Compound 47: 9-(6-(4-Benzylpiperazin-1-yl)hexyl)-9H-carbazole

Compound 48: 2-(4-(6-(9H-carbazol-9-yl)hexyl)piperazin-1-yl)phenol

Compound 49: 9-(6-(4-(2-Methoxyphenyl)piperazin-1-yl)hexyl)-9H-carbazole

Compound 50: 9-(5-(4-Phenylpiperidin-1-yl)pentyl)-9H-carbazole

Compound 51: 9-(5-(4-Benzylpiperazin-1-yl)pentyl)-9H-carbazole

Compound 52: 2-(4-(5-(9H-carbazol-9-yl)pentyl)piperazin-1-yl)phenol

Compound 53:9-(5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl)-9H-carbazole

Compound 54: 9-(4-(4-Phenylpiperidin-1-yl)butyl)-9H-carbazole

Compound 55: 2-(4-(4-(9H-carbazol-9-yl)butyl)piperazin-1-yl)phenol

Compound 56: 9-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-9H-carbazole

Compound 57: 9-(3-(4-Phenylpiperidin-1-yl)propyl)-9H-carbazole

Compound 58: 9-(3-(4-Benzylpiperazin-1-yl)propyl)-9H-carbazole

Compound 59: 2-(4-(3-(9H-carbazol-9-yl)propyl)piperazin-1-yl)phenol

and

Compound 60:9-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-9H-carbazole

In a further aspect, the present invention provides a method forpreparing a carbazole compound represented by Formula 1:

wherein X, Y, and n are as defined above, the method including reactinga compound represented by Formula 6:

wherein X and n are as defined above, with a compound represented byFormula 7:

Y—H  (7)

wherein Y is as defined above, in an organic solvent.

The organic solvent may be selected from the group consisting ofacetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, loweralcohol, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate,dioxane, chloroform, benzene, and toluene.

The reaction may be carried out under reflux at 25 to 300° C. for 3 to24 hours.

The reaction may be carried out in the presence of a base for improvedreactivity. The base may be selected from K₂CO₃, triethylamine, anddiisopropylethylamine.

In the present invention, the lower alcohol may be methanol, ethanol,propanol or butanol.

According to one embodiment of the present invention, the reactionmixture may be extracted with a suitable organic solvent known in theart. Specifically, the reaction mixture is diluted with an organicsolvent selected from dichloromethane, diethyl ether, and ethyl acetate,a weakly acidic aqueous solution is added thereto, the organic layer isseparated from the aqueous layer, the remaining water molecules areremoved from the organic layer, followed by concentration andpurification.

The purification may be performed by any suitable technique known in theart, preferably column chromatography on silica gel, to obtain thedesired carbazole derivative represented by Formula 1.

The pharmaceutically acceptable salt of the carbazole derivativerepresented by Formula 1 may be prepared using a non-toxic inorganic ororganic acid. Examples of suitable non-toxic inorganic acids includehydrochloric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid,phosphoric acid, and nitric acid. Examples of suitable non-toxic organicacids include acetic acid, propionic acid, succinic acid, glycolic acid,stearic acid, lactic acid, tartaric acid, citric acid,para-toluenesulfonic acid, and methanesulfonic acid.

According to one embodiment of the present invention, the compound ofFormula 6 may be prepared by reacting carbazole with a compound ofFormula 8:

wherein X and n are as defined above, in an organic solvent.

The organic solvent may be selected from the group consisting ofacetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, loweralcohol, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate,dioxane, chloroform, benzene, and toluene.

The reaction may be carried out under reflux at 25 to 200° C. for 3 to24 hours. The desired compound may be obtained by any suitablepurification technique known in the art. Preferably, the carbazolecompound of Formula 6 is purified by column chromatography on silicagel.

According to one embodiment of the present invention, when X in Formula8 is CH₂, the reaction for the preparation of the compound of Formula 6may be carried out in the presence of a base. The base may be selectedfrom t-BuOK, triethylamine, and diisopropylethylamine. When X is C(O),the reaction for the preparation of the compound of Formula 6 ispreferably carried out in the dark, where improved reactivity is ensuredand side reactions are prevented.

In another aspect, the present invention provides a pharmaceuticalcomposition for preventing and treating a central nervous systemdisease, including the carbazole compound represented by Formula 1 orpharmaceutically acceptable salt thereof as an active ingredient.

The central nervous system disease may be selected from the groupconsisting of depression, migraine, anxiety, pain, inflammatory pain,neuropathic pain, body temperature dysregulation, circadian rhythmdysregulation, sleep disturbance, smooth muscle-related diseases, andcombinations thereof.

The pharmaceutical composition of the present invention has a bindingaffinity for the 5-HT₇ receptor and exhibits an inhibitory activityagainst the 5-HT₇ receptor due to its selective antagonism against the5-HT₇ receptor.

According to one embodiment of the present invention, the carbazolecompound or pharmaceutically acceptable salt thereof may be mixed with acarrier, excipient or diluent known in the art and the mixture may beformulated into a dosage form suitable for oral or parenteraladministration by any suitable technique known in the art.

Examples of such carriers, excipients or diluents include lactose,dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol,starch, alginate, gelatin, calcium phosphate, calcium silicate,cellulose, methyl cellulose, microcrystalline cellulose,polyvinylpyrrolidone, water, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

For formulation, the pharmaceutical composition may further include atleast one additive selected from fillers, extenders, binders, wettingagents, disintegrants, and surfactants known in the art. A lubricatingagent such as magnesium stearate or talc may be further added duringformulation.

For oral administration, the pharmaceutical composition may be in theform of tablets, capsules, solutions, suspensions, and the like. Forparenteral administration, the pharmaceutical composition may be in theform of preparations for intraperitoneal, subcutaneous, intramuscular,and transdermal injections.

According to one embodiment of the present invention, the pharmaceuticalcomposition is a 5-HT₇ serotonin receptor modulator. The pharmaceuticalcomposition is administered in an amount such that the effective dose ofthe carbazole derivative of Formula 1 or pharmaceutically acceptablesalt thereof ranges from 0.01 to 1000 mg/day for an adult. The dailydose may depend on the age, weight, sex, and general health of thepatient, the mode of administration, and the severity of diseases to betreated. The daily dose may be administered in a single dose or individed doses at regular time intervals according to the judgment of thephysician or pharmacist.

Thus, the present invention provides the medical use of the carbazolecompound represented by Formula 1 or pharmaceutically acceptable saltthereof or the pharmaceutical composition for the prevention andtreatment of diseases.

Specifically, the present invention includes the medical use of thecarbazole compound represented by Formula 1 or pharmaceuticallyacceptable salt thereof or the pharmaceutical composition, which acts asa 5-HT₇ serotonin receptor modulator, for the prevention and treatmentof neurological diseases, such as depression, migraine, anxiety, andpain, particularly inflammatory pain and neuropathic pain, bodytemperature dysregulation, circadian rhythm dysregulation, sleepdisturbance, and smooth muscle-related diseases.

The present invention will be explained in more detail with reference tothe following examples. However, it will be obvious to those skilled inthe art that these examples are provided for illustrative purposes onlyand are not intended to limit the scope of the invention.

EXAMPLES Example 11 6-Bromo-1-(9H-carbazol-9-yl)hexan-1-one

Carbazole (2 g, 11.96 mmol) was dissolved in toluene (100 ml) in thereactor, which was covered with a foil to prevent light from entering.To the solution was added 6-bromohexanoyl chloride (5.1 g, 23.92 mmol).The mixture was heated to reflux at 115° C. for 18 h. After completionof the reaction, the reaction solution was concentrated under reducedpressure and diluted with CH₂C₁₂. The diluted solution was washed with 1N HCl and H₂O, dried over anhydrous Na₂SO₄, and filtered. The filtratewas concentrated under reduced pressure. The resulting concentrate waspurified by silica gel column chromatography (hexane:EtOAc=20:1), giving3.4 g (9.88 mmol, 83% yield) of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.77 (dd, J=7.7 Hz, J=1.2 Hz, 1H), 7.64 (td,J=7.7 Hz, J=1.2 Hz, 1H), 7.58-7.42 (m, 7H)

Example 12 5-Bromo-1-(9H-carbazol-9-yl)pentan-1-one

The title compound was prepared in the same manner as in Example 1.1,except that 5-bromopentanoyl chloride was used instead of6-bromohexanoyl chloride.

Example 13 4-Bromo-1-(9H-carbazol-9-yl)butan-1-one

The title compound was prepared in the same manner as in Example 1.1,except that 4-bromobutanoyl chloride was used instead of 6-bromohexanoylchloride.

Example 14 9-(6-Bromohexyl)-9H-carbazole

Carbazole (2 g, 11.96 mmol), 1,6-dibromohexane (2.8 ml, 17.94 mmol), andt-BuOK (1.3 g, 11.96 mmol) were dissolved in THF (15 ml) in a reactor.The solution was stirred under heating at 40° C. for 10 h. Aftercompletion of the reaction, the reaction solution was concentrated underreduced pressure and diluted with CH₂C₁₂. The diluted solution waswashed with H₂O, dried over anhydrous Na₂SO₄, and filtered. The filtratewas concentrated under reduced pressure. The concentrate was purified bysilica gel column chromatography (hexane:MC=8:1), giving 2.1 g (6.36mmol, 53% yield) of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 8.03-8.01 (m, 2H), 7.39-7.35 (m, 2H), 7.25 (d,J=8.2 Hz, 2H), 7.15 (td, J=7.4 Hz, J=0.8 Hz, 2H), 4.07 (t, J=7.1 Hz,2H), 3.17 (t, J=6.7 Hz, 2H), 1.72-1.57 (m, 4H), 1.30-1.14 (m, 4H)

Example 15 9-(5-Bromopentyl)-9H-carbazole

The title compound was prepared in the same manner as in Example 1.4,except that 1,5-dibromopentane was used instead of 1,6-dibromohexane.

Example 16 9-(4-Bromobutyl)-9H-carbazole

The title compound was prepared in the same manner as in Example 1.4,except that 1,4-dibromobutane was used instead of 1,6-dibromohexane.

Example 17 9-(3-Bromopropyl)-9H-carbazole

The title compound was prepared in the same manner as in Example 1.4,except that 1,3-dibromopropane was used instead of 1,6-dibromohexane.

Example 2 Example 2.16-(Butyl(methyl)amino)-1-(9H-carbazol-9-yl)hexan-1-one hydrochloride

The compound of Example 1.1 (100 mg, 0.29 mmol) and N-methylbutylamine(0.02 ml, 0.35 mmol) were dissolved in acetonitrile (10 ml) in areactor. The solution was heated to reflux at 85° C. for 21 h. Aftercompletion of the reaction, the reaction mixture was diluted withCH₂C₁₂, and 0.5 N HCl and H₂O were then added thereto. The aqueous layerwas extracted with CH₂C₁₂. The obtained organic layer was dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure. The concentrate was purified by silica gel columnchromatography (MC:MeOH=20:1). The crude product was added dropwise to asolution of 0.5 N hydrochloric acid (0.30 ml, 0.34 mmol) in dimethylether to obtain a solid precipitate. Filtration of the precipitate gave64.4 mg (0.17 mmol, 57% yield) of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 11.57 (brs, 0.8H), 8.21 (d, J=8.4 Hz, 2H),7.99 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.48 (td, J=7.8 Hz, J=1.2 Hz, 2H),7.38 (t, J=7.2 Hz, 2H), 3.19 (t, J=6.7 Hz, 2H), 3.11-2.90 (m, 4H), 2.76(d, J=4.6 Hz, 3H), 2.04-1.77 (m, 6H), 1.63-1.58 (m, 2H), 1.45-1.36 (m,2H), 0.97 (t, J=7.3 Hz, 3H)

Example 2.2 6-(Benzyl)methyl)amino)-1-(9H-carbazol-9-yl)hexan-1-onehydrochloride

70.0 mg (0.17 mmol, 57% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and N-benzylmethylamine(0.04 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 12.08 (brs, 0.8H), 8.22 (d, J=8.4 Hz, 2H),8.00 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.61-7.59 (m, 2H), 7.51-7.38 (m, 7H),4.18 (brd, J=12.6 Hz, 2H), 3.18 (t, J=6.7 Hz, 2H), 3.12 (brs, 1H), 2.89(brs, 1H), 2.69 (s, 3H), 2.12 (brs, 1H), 1.97 (quint, J=7.1 Hz, 3H),1.58 (brs, 2H)

Example 2.3 1-(9H-carbazol-9-yl)-6-(pyrrolidin-1-yl)hexan-1-onehydrochloride

98.0 mg (0.26 mmol, 91% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and pyrrolidine (0.03ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (300 MHz, CDCl₃) δ 11.85 (brs, 0.8H), 8.22 (d, J=8.2 Hz, 2H),8.00 (d, J=7.2 Hz, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H),3.82 (brs, 2H), 3.19 (t, J=6.3 Hz, 2H), 3.09 (brs, 2H), 2.79 (brs, 2H),2.26 (brs, 2H), 2.06-1.99 (m, 6H), 1.64 (s, 2H)

Example 2.4 1-(9H-carbazol-9-yl)-6-(4-methylpiperidin-1-yl)hexan-1-one

The compound of Example 1.1 (100 mg, 0.29 mmol) and 4-methylpiperidine(0.04 ml, 0.35 mmol) were dissolved in acetonitrile (10 ml) in areactor. The solution was heated to reflux at 85° C. for 21 h. Aftercompletion of the reaction, the reaction mixture was diluted withCH₂C₁₂, and 0.5 N HCl and H₂O were then added thereto. The aqueous layerwas extracted with CH₂C₁₂. The obtained organic layer was dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure. The concentrate was purified by silica gel columnchromatography (hexane:EtOAc=4:1), giving 51 mg (0.14 mmol, 48% yield)of the final title compound.

¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=8.3 Hz, 2H), 8.02-7.99 (m, 2H),7.51-7.45 (m, 2H), 7.38 (td, J=7.5 Hz, J=0.9 Hz, 2H), 3.16 (t, J=7.4 Hz,2H), 2.91 (brd, J=11.7 Hz, 2H), 2.36 (t, J=7.6 Hz, 2H), 2.04-1.83 (m,4H), 1.67-1.47 (m, 6H), 1.38-1.19 (m, 3H), 0.92 (d, J=6.0 Hz, 3H)

Example 2.5 1-(9H-carbazol-9-yl)-6-(3-methylpiperidin-1-yl)hexan-1-onehydrochloride

63.6 mg (0.16 mmol, 55% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and 3-methylpiperidine(0.04 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.22 (brs, 0.8H), 8.23 (d, J=8.4 Hz, 2H),8.01 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.52-7.47 (m, 2H), 7.39 (t, J=7.3 Hz,2H), 3.57 (brd, J=10.2 Hz, 1H), 3.49-3.43 (m, 1H), 3.20 (t, J=6.7 Hz,2H), 2.98-2.97 (m, 2H), 2.54-2.37 (m, 3H), 2.21 (q, J=10.9 Hz, 1H),2.08-1.85 (m, 7H), 1.59 (s, 1H), 1.14-1.04 (m, 1H), 0.96 (d, J=6.6 Hz,3H)

Example 2.61-(9H-carbazol-9-yl)-6-(3,5-dimethylpiperidin-1-yl)hexan-1-onehydrochloride

82.5 mg (0.20 mmol, 69% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and3,5-dimethylpiperidine (0.05 ml, 0.35 mmol) in accordance with theprocedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.64 (brs, 0.8H) 8.22 (d, J=8.3 Hz, 2H), 8.00(d, J=7.6 Hz, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 3.40(brd, J=9.2 Hz, 2H), 3.19 (t, J=6.2 Hz, 2H), 2.96 (brs, 2H), 2.52 (brs,2H), 2.16-1.90 (m, 7H), 1.58 (brs, 3H), 0.95 (d, J=6.3 Hz, 6H);

Example 2.7 6-(Azepan-1-yl)-1-(9H-carbazol-9-yl)hexan-1-onehydrochloride

95.7 mg (0.24 mmol, 83% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and hexamethyleneimine(0.04 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (300 MHz, CDCl₃) δ 11.53 (brs, 0.8H), 8.22 (d, J=8.3 Hz, 2H),8.00 (d, J=7.6 Hz, 2H), 7.49 (t, J=7.8 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H),3.56-3.54 (m, 2H), 3.19 (t, J=6.7 Hz, 2H), 3.03-2.88 (m, 4H), 2.22-2.15(m, 2H), 2.04-1.94 (m, 4H), 1.87-1.81 (m, 4H), 1.61 (s, 4H)

Example 2.8 1-(9H-carbazol-9-yl)-6-morpholinohexan-1-one hydrochloride

31.6 mg (0.08 mmol, 28% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and morpholine (0.03 ml,0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 12.75 (brs, 0.8H), 8.22 (brd, J=6.7 Hz, 2H),8.00 (d, J=7.6 Hz, 2H), 7.49 (brs, 2H), 7.39 (t, J=7.2 Hz, 2H), 4.36(brs, 2H), 3.99 (brs, 2H), 3.49-3.45 (m, 2H), 3.20 (brs, 2H), 3.04 (brs,2H), 2.88 (brs, 2H), 2.05 (brd, J=30.7 Hz, 4H), 1.60 (s, 2H)

Example 2.9 1-(9H-carbazol-9-yl)-6-(4-phenylpiperidin-1-yl)hexan-1-onehydrochloride

45.6 mg (0.10 mmol, 34% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and 4-phenylpiperidine(56 mg, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.95 (brs, 0.8H), 8.23 (d, J=8.4 Hz, 2H),8.01 (dd, J=5.7 Hz, J=0.8 Hz, 2H), 7.52-7.48 (m, 2H), 7.40 (t, J=7.5 Hz,2H), 7.34-7.23 (m, 5H), 3.70 (brd, J=10.2 Hz, 2H), 3.21 (t, J=6.7 Hz,2H), 3.04 (brs, 2H), 2.80-2.65 (m, 4H), 2.11 (brs, 3H), 2.02 (brd,J=11.0 Hz, 3H), 1.63-1.58 (m, 3H)

Example 2.10 6-(4-Benzylpiperidin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-onehydrochloride

88.4 mg (0.19 mmol, 64% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and 4-benzylpiperidine(0.06 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.51 (brs, 0.8H), 8.22 (brs, 2H), 7.99 (brd,J=6.6 Hz, 2H), 7.49 (brs, 2H), 7.38 (brs, 2H), 7.29 (brs, 2H), 7.22(brs, 1H), 7.14 (brs, 2H), 3.66 (brs, 2H), 3.19 (brs, 2H), 3.03 (brs,2H), 2.64 (s, 4H), 2.10 (brd, J=59.6 Hz, 6H), 1.85 (brs, 3H), 1.71 (s,2H)

Example 2.11 6-(4-Acetylpiperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-onehydrochloride

55.4 mg (0.13 mmol, 45% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and acetylpiperazine (45mg, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, MeOD) δ 8.24 (brs, 2H), 8.05 (brs, 2H), 7.47 (brs, 2H),7.38 (brd, J=3.3 Hz, 2H), 4.64 (brd, J=12.9 Hz, 1H), 4.12 (brs, 1H),3.59 (brs, 4H), 3.24-2.99 (m, 4H), 2.15 (s, 3H), 1.92 (brd, J=32.3 Hz,5H), 1.59 (brs, 3H)

Example 2.12 1-(9H-carbazol-9-yl)-6-(4-methylpiperazin-1-yl)hexan-1-onehydrochloride

83.8 mg (0.21 mmol, 72% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and methylpiperazine(0.03 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, MeOD) δ 8.26 (d, J=8.4 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H),7.51-7.47 (m, 2H), 7.39 (t, J=7.4 Hz, 2H), 3.48-3.24 (m, 10H), 2.99(brs, 2H), 2.78 (s, 3H), 1.96 (quint, J=7.3 Hz, 2H), 1.79 (brs, 2H),1.58 (quint, J=7.5 Hz, 2H)

Example 2.13 6-(4-Benzylpiperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-onehydrochloride

135.0 mg (0.28 mmol, 98% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and benzylpiperazine(0.06 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, DMSO) δ 11.48 (brs, 0.8H), 8.27 (d, J=8.4 Hz, 2H), 8.19(dd, J=5.7 Hz, J=0.7 Hz, 2H), 7.60 (brs, 2H), 7.54-7.49 (m, 2H),7.45-7.40 (m, 5H), 4.32 (brs, 2H), 3.66 (brs, 2H), 3.42 (s, 4H), 3.27(t, J=7.0 Hz, 4H), 3.11 (brs, 2H), 1.83-1.77 (m, 4H), 1.49-1.47 (m, 2H)

Example 2.146-(4-Benzo[d]isoxazol-3-yl)piperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-onehydrochloride

6.3 mg (0.01 mmol, 4% yield) of the title compound was prepared usingthe compound of Example 1.1 (100 mg, 0.29 mmol) and3-(1-piperazinyl)-1,2-benzisoxazole (71 mg, 0.35 mmol) in accordancewith the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 13.21 (brs, 0.8H), 8.20 (brd, J=6.4 Hz, 2H),7.99 (d, J=7.5 Hz, 2H), 7.61 (brs, 2H), 7.55-7.48 (m, 4H), 7.38 (t,J=7.1 Hz, 2H), 4.15 (brs, 4H), 3.56 (brs, 2H), 3.19 (brs, 2H), 3.05(brs, 5H), 2.08-1.99 (m, 5H)

Example 2.151-(9H-carbazol-9-yl)-6-(4-(2-hydroxyphenyl)piperazin-1-yl)hexan-1-one

195 mg (0.44 mmol, 76% yield) of the title compound was prepared using1-(2-hydroxyphenyl)piperazine (124 mg, 0.70 mmol), the compound ofExample 1.1 (200 mg, 0.58 mmol), and K₂CO₃ (80 mg, 0.58 mmol) inaccordance with the procedure of Example 2.4.

¹H NMR (300 MHz, CDCl₃) δ 8.24 (d, J=9.0 Hz, 2H), 8.02 (dd, J=7.6, 0.7Hz, 2H), 7.49 (td, J=7.8, 1.4 Hz, 2H), 7.40 (td, J=7.4, 0.8 Hz, 2H),7.17 (dd, J=7.8, 1.2 Hz, 1H), 7.10-7.05 (m, 1H), 6.95 (dd, J=8.1, 1.5Hz, 1H), 6.88-6.83 (m, 1H), 3.19 (t, J=7.4 Hz, 2H), 2.91 (brt, J=4.5 Hz,4H), 2.63 (brs, 4H), 2.47 (t, J=7.2 Hz, 2H), 2.05-1.94 (m, 2H),1.66-1.53 (m, 4H)

Example 2.161-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one

21 mg (0.046 mmol, 77% yield) of the title compound was prepared using1-(2-methoxyphenyl)piperazine (13.4 mg, 0.07 mmol), the compound ofExample 1.1 (20 mg, 0.06 mmol), and K₂CO₃ (8 mg, 0.06 mmol) inaccordance with the procedure of Example 2.4.

¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J=8.4 Hz, 2H), 7.99 (dt, J=7.6, 0.7Hz, 2H), 7.50-7.45 (m, 2H), 7.38 (td, J=7.4, 1.0 Hz, 2H), 7.02-6.92 (m,4H), 3.86 (s, 3H), 3.17-3.12 (m, 6H), 2.66 (brs, 4H), 2.46 (t, J=7.5 Hz,2H), 2.02-1.92 (m, 2H), 1.68-1.51 (m, 4H)

Example 2.17 5-(Butyl(methyl)amino)-1-(9H-carbazol-9-yl)pentan-1-onehydrochloride

82.0 mg (0.22 mmol, 73% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and N-methylbutylamine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.41 (brs, 0.8H), 8.19 (d, J=8.3 Hz, 2H),7.99 (d, J=7.5 Hz, 2H), 7.47 (t, J=7.5 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H),3.25 (t, J=6.0 Hz, 2H), 3.17-3.06 (m, 5H), 2.77 (s, 3H), 2.12 (brs, 2H),2.02-2.00 (m, 2H), 1.90 (brs, 1H), 1.80 (brs, 1H), 1.40 (brd, J=6.7 Hz,2H), 0.97 (t, J=7.3 Hz, 3H)

Example 2.18 5-(Benzyl(methyl)amino)-1-(9H-carbazol-9-yl)pentan-1-onehydrochloride

90.7 mg (0.22 mmol, 74% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and N-benzylmethylamine(0.05 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 12.72 (brs, 0.8H), 8.20 (d, J=8.2 Hz, 2H),8.01 (dd, J=5.7 Hz, J=0.8 Hz, 2H), 7.62 (brd, J=3.4 Hz, 2H), 7.51-7.38(m, 7H), 4.20 (q, J=14.0 Hz, 2H), 3.23-3.17 (m, 3H), 2.93 (brs, 1H),2.72 (s, 3H), 2.18 (brd, J=33.3 Hz, 2H), 1.98 (brs, 2H)

Example 2.19 1-(9H-carbazol-9-yl)-5-(pyrrolidin-1-yl)pentan-1-onehydrochloride

38.7 mg (0.11 mmol, 36% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and pyrrolidine (0.03ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.66 (brs, 0.8H), 8.20 (d, J=8.3 Hz, 2H),8.00 (d, J=7.2 Hz, 2H), 7.51-7.46 (m, 2H), 7.39 (t, J=7.3 Hz, 2H),3.86-3.84 (m, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.19-3.13 (m, 2H), 2.86-2.78(m, 2H), 2.28-1.97 (m, 8H)

Example 2.20 1-(9H-carbazol-9-yl)-5-(4-methylpiperidin-1-yl)pentan-1-onehydrochloride

44.2 mg (0.11 mmol, 38% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and 4-methylpiperidine(0.04 ml, 0.30 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.89 (brs, 0.8H), 8.20 (d, J=8.4 Hz, 2H),7.99 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.48 (td, J=7.8 Hz, J=1.2 Hz, 2H),7.41-7.37 (m, 2H), 3.59 (brd, J=11.4 Hz, 2H), 3.25 (t, J=6.7 Hz, 2H),3.02 (quint, J=5.3 Hz, 2H), 2.63 (q, J=10.8 Hz, 2H), 2.18-2.13 (m, 2H),2.09-1.94 (m, 5H), 1.81 (brd, J=14.0 Hz, 2H), 1.07-1.03 (m, 3H)

Example 2.21 1-(9H-carbazol-9-yl)-5-(3-methylpiperidin-1-yl)pentan-1-onehydrochloride

59.5 mg (0.15 mmol, 51% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and 3-methylpiperidine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.26 (brs, 0.8H) 8.20 (d, J=8.4 Hz, 2H), 7.98(d, J=7.1 Hz, 2H), 7.50-7.45 (m, 2H), 7.38 (t, J=7.3 Hz, 2H), 3.58 (brd,J=10.4 Hz, 1H), 3.48-3.44 (m, 1H), 3.24 (t, J=6.7 Hz, 2H), 3.05 (brt,J=7.6 Hz, 2H), 2.58-2.14 (m, 6H), 2.00-1.85 (m, 5H), 0.95 (m, J=6.2 Hz,3H)

Example 2.221-(9H-carbazol-9-yl)-5-(3,5-dimethylpiperidin-1-yl)pentan-1-onehydrochloride

60.6 mg (0.15 mmol, 50% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and3,5-dimethylpiperidine (0.05 ml, 0.36 mmol) in accordance with theprocedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 12.16 (brs, 0.8H), 8.19 (d, J=8.3 Hz, 2H),7.99 (d, J=7.3 Hz, 2H), 7.49-7.45 (m, 2H), 7.38 (t, J=7.3 Hz, 2H), 3.41(brd, J=11.0 Hz, 2H), 3.24 (t, J=6.7 Hz, 2H), 3.01 (brt, J=7.9 Hz, 2H),2.47 (brs, 2H), 2.16-2.09 (m, 4H), 1.97 (quint, J=7.2 Hz, 2H), 1.89(brd, J=13.2 Hz, 2H), 0.94 (d, J=6.6 Hz, 6H)

Example 2.23 5-(Azepan-1-yl)-1-(9H-carbazol-9-yl)pentan-1-onehydrochloride

37.0 mg (0.10 mmol, 32% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and hexamethyleneimine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.39 (brs, 0.8H), 8.19 (d, J=8.3 Hz, 2H),7.98 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.47 (t, J=7.3 Hz, 2H), 7.38 (t,J=7.4 Hz, 2H), 3.58 (brs, 2H), 3.24 (t, J=6.0 Hz, 2H), 3.09 (brs, 2H),2.95 (brs, 2H), 2.18 (s, 4H), 1.98-1.97 (m, 2H), 1.86-1.83 (m, 4H), 1.63(s, 2H)

Example 2.24 1-(9H-carbazol-9-yl)-5-morpholinopentan-1-one hydrochloride

80.7 mg (0.22 mmol, 71% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and morpholine (0.03 ml,0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 12.94 (brs, 0.8H), 8.18 (d, J=8.2 Hz, 2H),7.98 (d, J=7.3 Hz, 2H), 7.47 (t, J=7.5 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H),4.32 (t, J=12.0 Hz, 2H). 3.97 (d, J=11.6 Hz, 2H), 3.48-3.43 (m, 2H),3.25 (s, 2H), 3.07 (s, 2H), 2.88 (s, 2H), 2.17 (s, 2H), 2.00 (s, 2H)

Example 2.25 1-(9H-carbazol-9-yl)-5-(4-phenylpiperidin-1-yl)pentan-1-onehydrochloride

109.2 mg (0.24 mmol, 81% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and 4-phenylpiperidine(73 mg, 0.45 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.67 (brs, 0.8H), 8.21 (d, J=8.4 Hz, 2H),7.99 (dd, J=5.8 Hz, J=0.8 Hz, 2H), 7.50-7.46 (m, 2H), 7.38 (td, J=7.5Hz, J=0.7 Hz, 2H), 7.34-7.19 (m, 5H), 3.73 (brd, =10.4 Hz, 2H), 3.27 (t,J=6.7 Hz, 2H), 3.12-3.07 (m, 2H), 2.86-2.64 (m, 5H), 2.27-2.19 (m, 2H),2.04-1.97 (m, 4H)

Example 2.26 5-(4-Benzylpiperidin-1-yl)-1-(9H-carbazol-9-yl)pentan-1-onehydrochloride

113.5 mg (0.25 mmol, 81% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and 4-benzylpiperidine(0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 12.15 (brs, 0.8H), 8.18 (d, J=8.1 Hz, 2H),7.98 (d, J=7.6 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.4 Hz, 2H),7.29-7.17 (m, 3H), 7.11 (d, J=7.2 Hz, 2H), 3.57 (brd, J=9.8 Hz, 2H),3.23 (s, 2H), 2.99 (s, 2H), 2.66-2.55 (m, 4H), 2.15-2.05 (m, 4H), 1.96(s, 2H), 1.80 (d, J=13.5 Hz, 2H), 1.70 (brs, 1H)

Example 1.27 5-(4-Acetylpiperazin-1-yl)-1-(9H-carbazol-9-yl)pentan-1-onehydrochloride

117.4 mg (0.28 mmol, 94% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and acetylpiperazine (47mg, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, DMSO) δ 9.52 (brs, 0.8H), 8.29 (d, J=8.4 Hz, 2H), 8.21(dd, J=5.8 Hz, J=0.8 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.41 (m, 2H), 4.42(brd, J=9.2 Hz, 1H), 4.01 (brd, J=14.4 Hz, 1H), 3.50 (brd, J=8.0 Hz,2H), 3.41-3.32 (m, 2H), 3.20 (s, 2H), 3.04 (brd, J=10.0 Hz, 2H), 2.91(brd, J=8.4 Hz, 2H), 2.03 (s, 3H), 1.83 (s, 4H)

Example 2.28 1-(9H-carbazol-9-yl)-5-(4-methylpiperazin-1-yl)pentan-1-onehydrochloride

91.0 mg (0.24 mmol, 78% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and methylpiperazine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, DMSO) δ 11.61 (brs, 0.8H), 8.29 (d, J=8.4 Hz, 2H), 8.20(dd, J=5.8 Hz, J=0.8 Hz, 2H), 7.55-7.50 (m, 2H), 7.44-7.40 (m, 2H), 3.32(s, 9H), 3.16 (s, 3H), 2.72 (brs, 3H), 1.83 (s, 4H)

Example 2.29 5-(4-Benzylpiperazinyl)-1-(9H-carbazol-9-yl)pentan-1-onehydrochloride

28.3 mg (0.06 mmol, 20% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and benzylpiperazine(0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, MeOD) δ 8.30 (d, J=8.4 Hz, 2H), 8.09 (d, J=7.6 Hz, 2H),7.56 (brd, J=3.1 Hz, 2H), 7.52-7.48 (m, 5H), 7.43-7.39 (m, 2H), 4.34 (s,2H), 3.82-3.21 (m, 12H), 2.00 (t, J=3.1 Hz, 4H)

Example 2.301-(9H-carbazol-9-yl)-5-(4-(2-hydroxyphenyl)piperazin-1-yl)pentan-1-onehydrochloride

65.8 mg (0.14 mmol, 23% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and1-(2-hydroxyphenyl)piperazine (162 mg, 0.91 mmol) in accordance with theprocedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 10.22 (brs, 0.8H), 8.31 (d, J=8.4 Hz, 2H),8.20 (dd, J=5.7 Hz, J=0.8 Hz, 2H), 7.53 (td, J=7.8 Hz, J=1.2 Hz, 2H),7.43 (t, J=7.2 Hz, 2H), 6.90-6.81 (m, 3H), 6.75 (td, J=7.4 Hz, J=1.6 Hz,1H), 3.47 (brd, J=12.8 Hz, 3H), 3.39-3.33 (m, 4H), 3.22-3.15 (m, 4H),3.00 (t, J=11.5 Hz, 2H), 1.89-1.85 (m, 4H)

Example 2.311-(9H-carbazol-9-yl)-5-(4-(2-methoxyphenyl)piperazin-1-yl)pentan-1-onehydrochloride

43.1 mg (0.09 mmol, 30% yield) of the title compound was prepared usingthe compound of Example 1.2 (100 mg, 0.30 mmol) and1-(2-methoxyphenyl)piperazine (0.06 ml, 0.36 mmol) in accordance withthe procedure of Example 2.1.

¹H NMR (300 MHz, DMSO) δ 10.62 (brs, 0.8H), 8.32 (d, J=8.3 Hz, 2H), 8.22(d, J=7.5 Hz, 2H), 7.56-7.51 (m, 2H), 7.43 (t, J=7.4 Hz, 2H), 7.05-6.87(m, 4H), 3.79 (s, 3H), 3.53 (q, J=10.4 Hz, 4H), 3.35 (t, J=6.3 Hz, 2H),3.23-3.02 (m, 6H), 1.91-1.85 (m, 4H)

Example 2.32 4-(4-Benzylpiperazin-1-yl)-1-(9H-carbazol-9-yl)butan-1-onehydrochloride

27.7 mg (0.06 mmol, 17% yield) of the title compound was prepared usingthe compound of Example 1.3 (100 mg, 0.37 mmol) and benzylpiperazine(0.08 ml, 0.44 mmol) in accordance with the procedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 11.47 (brs, 0.8H), 8.33 (d, J=8.4 Hz, 2H),8.20 (d, J=7.0 Hz, 2H), 7.59 (s, 3H), 7.54-7.49 (m, 2H), 7.44-7.41 (m,4H), 4.30 (brs, 4H), 3.73-3.08 (m, 6H), 2.42 (t, J=7.3 Hz, 2H),2.21-2.20 (m, 2H), 1.95-1.89 (m, 2H)

Example 2331-(9H-carbazol-9-yl)-4-(4-(2-hydroxyphenyl)piperazin-1-yl)butan-1-one

148.1 mg (0.36 mmol, 49% yield) of the title compound was prepared usingthe compound of Example 1.3 (200 mg, 0.74 mmol) and1-(2-hydroxyphenyl)piperazine (197 mg, 1.10 mmol) in accordance with theprocedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J=8.4 Hz, 2H), 8.03-8.01 (m, 2H),7.52-7.47 (m, 2H), 7.40 (td, J=7.5 Hz, J=0.8 Hz, 2H), 7.08-7.03 (m, 2H),6.93 (dd, J=6.0 Hz, J=1.2 Hz, 1H), 6.85-6.81 (m, 1H), 3.25 (t, J=7.0 Hz,2H), 2.81 (t, J=4.7 Hz, 4H), 2.61 (t, J=7.0 Hz, 6H), 2.17 (quint, J=7.0Hz, 2H)

Example 2.341-(9H-carbazol-9-yl)-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-1-one

78 mg (0.18 mmol, 50% yield) of the title compound was prepared usingthe compound of Example 1.3 (100 mg, 0.37 mmol) and1-(2-hydroxyphenyl)piperazine (197 mg, 1.10 mmol) in accordance with theprocedure of Example 2.1.

¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=8.4 Hz, 2H), 7.98 (d, J=7.6 Hz,2H), 7.48-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.00-6.94 (m, 1H),6.92-6.87 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 3.21 (t, J=7.1 Hz, 2H), 3.06(s, 4H), 2.69 (s, 4H), 2.60 (t, J=7.0 Hz, 2H), 2.16 (quint, J=7.1 Hz,2H)

Example 2.35 N-Butyl-6-(9H-carbazol-9-yl)-N-methylhexane-1-amine

The compound of Example 1.4 (100 mg, 0.30 mmol) and N-methylbutylamine(0.04 ml, 0.36 mmol) were dissolved in acetonitrile (10 ml) in areactor. The solution was heated to reflux at 40° C. until the next day.After completion of the reaction, the reaction mixture was diluted withCH₂C₁₂, and H₂O were then added thereto. The aqueous layer was extractedwith CH₂C₁₂. The obtained organic layer was dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated under reduced pressure. Theconcentrate was purified by silica gel column chromatography(MC:MeOH=20:1), giving 68 mg (0.20 mmol, 67% yield) of the final titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.7 Hz, 2H), 7.45-7.40 (m, 2H),7.36 (d, J=8.2 Hz, 2H), 7.22-7.18 (m, 2H), 4.25 (t, J=6.9 Hz, 2H),2.82-2.71 (m, 4H), 2.54 (s, 3H), 1.83 (quint, J=7.2 Hz, 2H), 1.71-1.61(m, 4H), 1.35-1.20 (m, 6H), 0.90 (t, J=7.4 Hz, 3H)

Example 2.36 N-Benzyl-6-(9H-carbazol-9-yl)-N-methylhexane-1-amine

111.0 mg (0.30 mmol, 99% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and N-benzylmethylamine(0.05 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.6 Hz, 2H), 7.44-7.39 (m, 2H),7.34 (d, J=8.2 Hz, 2H), 7.29-7.24 (m, 4H), 7.23-7.17 (m, 3H), 4.21 (t,J=7.2 Hz, 2H), 3.40 (s, 2H), 2.26 (t, J=7.3 Hz, 2H), 2.11 (s, 3H), 1.80(quint, J=7.2 Hz, 2H), 1.42 (quint, J=7.1 Hz, 2H), 1.36-1.24 (m, 4H)

Example 2.37 9-(6-(Pyrrolidin-1-yl)hexyl)-9H-carbazole

61.4 mg (0.19 mmol, 63% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and pyrrolidine (0.03ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=7.7 Hz, 2H), 7.47-7.43 (m, 2H),7.38 (d, J=8.2 Hz, 2H), 7.23-7.19 (m, 2H), 4.28 (t, J=6.8 Hz, 2H), 3.07(brs, 3H), 2.78-2.74 (m, 2H), 2.04-2.02 (m, 4H), 1.84 (quint, J=7.2 Hz,2H), 1.75-1.67 (m, 2H), 1.36-1.22 (m, 5H)

Example 2.38 9-(6-(4-Methylpiperidin-1-yl)hexyl)-9H-carbazole

103 mg (0.30 mmol, 98% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and 4-methylpiperidine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H),7.37 (d, J=8.1 Hz, 2H), 7.22-7.18 (m, 2H), 4.26 (t, J=7.2 Hz, 2H), 2.83(brd, J=11.6 Hz, 2H), 2.22 (t, J=7.7 Hz, 2H), 1.88-1.80 (m, 4H), 1.58(brd, J=12.6 Hz, 2H), 1.48-1.17 (m, 9H), 0.89 (d, J=6.1 Hz, 3H)

Example 2.39 9-(6-(3-Methylpiperidin-1-yl)hexyl)-9H-carbazole

98.0 mg (0.28 mmol, 93% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and 3-methylpiperidine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=7.7 Hz, 2H), 7.46-7.42 (m, 2H),7.37 (d, J=8.2 Hz, 2H), 7.23-7.18 (m, 2H), 4.25 (t, J=7.1 Hz, 2H),2.89-2.82 (m, 2H), 2.28 (t, J=7.9 Hz, 2H), 1.86-1.58 (m, 8H), 1.55-1.45(m, 2H), 1.40-1.24 (m, 5H), 0.83 (d, J=6.5 Hz, 3H)

Example 2.40 9-(6-(3,5-Dimethylpiperidin-1-yl)hexyl)-9H-carbazole

91.3 mg (0.25 mmol, 83% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and3,5-dimethylpiperidine (0.05 ml, 0.36 mmol) in accordance with theprocedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H),7.35 (d, J=8.2 Hz, 2H), 7.20 (td, J=7.4 Hz, J=0.9 Hz, 2H), 4.23 (t,J=7.1 Hz, 2H), 2.80 (brdt, J=10.5 Hz, J=1.7 Hz, 2H), 2.25-2.21 (m, 2H),1.88-1.65 (m, 5H), 1.50-1.22 (m, 9H), 0.92 (d, J=6.8 Hz, 1H), 0.81 (d,J=6.5 Hz, 5H)

Example 2.41 9-(6-(Azepan-1-yl)hexyl)-9H-carbazole

57.5 mg (0.16 mmol, 54% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and hexamethyleneimine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H),7.36 (d, J=8.2 Hz, 2H), 7.22-7.18 (m, 2H), 4.25 (t, J=6.9 Hz, 2H), 3.03(brs, 3H), 2.75-2.71 (m, 2H), 1.86-1.63 (m, 12H), 1.35-1.18 (m, 5H)

Example 2.42 4-(6-(9H-carbazol-9-yl)hexyl)morpholine

97.0 mg (0.29 mmol, 95% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and morpholine (0.03 ml,0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.8 Hz, 2H), 7.42 (t, J=7.6 Hz,2H), 7.35 (d, J=8.1 Hz, 2H), 7.19 (t, J=7.4 Hz, 2H), 4.23 (t, J=7.1 Hz,2H), 3.66 (t, J=4.5 Hz, 4H), 2.33 (s, 4H), 2.21 (t, J=7.5 Hz, 2H), 1.82(quint, J=7.2 Hz, 2H), 1.43-1.27 (m, 6H)

Example 2.43 9-(6-(4-Phenylpiperidin-1-yl)hexyl)-9H-carbazole

92.9 mg (0.21 mmol, 69% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and 4-phenylpiperidine(59 mg, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06-8.04 (m, 2H), 7.44-7.39 (m, 2H), 7.34 (d,J=8.2 Hz, 2H), 7.27-7.16 (m, 7H), 4.22 (t, J=7.0 Hz, 2H), 3.15 (brd,J=11.6 Hz, 2H), 2.54-2.44 (m, 3H), 2.25 (brt, J=11.3 Hz, 2H), 2.16-2.05(m, 2H), 1.84-1.79 (m, 4H), 1.61-1.53 (m, 2H), 1.35-1.18 (m, 4H)

Example 2.44 9-(6-(4-Benzylpiperidin-1-yl)hexyl)-9H-carbazole

83.0 mg (0.18 mmol, 59% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and 4-benzylpiperidine(0.06 mg, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=7.7 Hz, 2H), 7.41 (td, J=7.6 Hz,J=1.1 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.25-7.13 (m, 5H), 7.10-7.08 (m,2H), 4.20 (t, J=7.1 Hz, 2H), 2.84 (brd, J=11.7 Hz, 2H), 2.48 (d, J=7.0Hz, 2H), 2.20 (t, J=7.9 Hz, 2H), 1.83-1.76 (m, 4H), 1.57 (brd, J=12.8Hz, 2H), 1.50-1.19 (m, 9H)

Example 2.45 1-(4-(6-(9H-carbazol-9-yl)hexyl)piperazin-1-yl)ethanone

103.6 mg (0.27 mmol, 91% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and acetylpiperazine (47mg, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=7.6 Hz, 2H), 7.44-7.40 (m, 2H),7.35 (d, J=8.2 Hz, 2H), 7.22-7.18 (m, 2H), 4.24 (t, J=7.1 Hz, 2H), 3.55(t, J=5.1 Hz, 2H), 3.34 (t, J=5.1 Hz, 2H), 2.27 (t, J=4.6 Hz, 4H), 2.20(t, J=7.4 Hz, 2H), 2.02 (s, 3H), 1.83 (quint, J=7.3 Hz, 2H), 1.41-1.21(m, 6H)

Example 2.46 9-(6-(4-Methylpiperazin-1-yl)hexyl)-9H-carbazole

62.0 mg (0.18 mmol, 59% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and methylpiperazine(0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=7.7 Hz, 2H), 7.44 (t, J=7.6 Hz,2H), 7.37 (d, J=8.1 Hz, 2H), 7.23-7.19 (m, 2H), 4.26 (t, J=7.1 Hz, 2H),2.43 (brs, 10H), 2.28-2.24 (m, 3H), 1.85 (quint, J=7.3 Hz, 2H),1.47-1.25 (m, 6H)

Example 2.47 9-(6-(4-Benzylpiperazin-1-yl)hexyl)-9H-carbazole

111.2 mg (0.24 mmol, 79% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and benzylpiperazine(0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.07-8.05 (m, 2H), 7.44-7.40 (m, 2H), 7.34 (d,J=8.2 Hz, 2H), 7.30-7.19 (m, 7H), 4.23 (t, J=7.2 Hz, 2H), 3.47 (s, 2H),2.42 (brs, 8H), 2.23 (t, J=7.6 Hz, 2H), 1.82 (quint, J=7.3 Hz, 2H),1.44-1.23 (m, 6H)

Example 2.48 2-(4-(6-(9H-carbazol-9-yl)hexyl)piperazin-1-yl)phenol

111.2 mg (0.26 mmol, 86% yield) of the title compound was prepared usingthe compound of Example 1.4 (100 mg, 0.30 mmol) and1-(2-hydroxyphenyl)piperazine (81 mg, 0.45 mmol) in accordance with theprocedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.7 Hz, 2H), 7.43-7.39 (m, 2H),7.34 (d, J=8.2 Hz, 2H), 7.20-7.16 (m, 2H), 7.10 (dd, J=5.9 Hz, J=1.5 Hz,1H), 7.02 (td, J=7.7 Hz, J=1.3 Hz, 1H), 6.92 (dd, J=6.0 Hz, J=1.4 Hz,1H), 6.81 (td, J=7.6 Hz, J=1.5 Hz, 1H), 4.21 (t, J=7.1 Hz, 2H), 2.83 (t,J=4.7 Hz, 4H), 2.48 (brs, 3H), 2.26 (t, J=7.6 Hz, 2H), 1.82 (quint,J=7.3 Hz, 2H), 1.44-1.25 (m, 7H)

Example 2.49 9-(6-(4-(2-Methoxyphenyl)piperazin-1-yl)hexyl)-9H-carbazole

650 mg (1.47 mmol, 49% yield) of the title compound was prepared using1-(2-methoxyphenyl)piperazine (699 mg, 3.64 mmol), the compound ofExample 1.4 (1 g, 3.03 mmol), and K₂CO₃ (418 mg, 3.03 mmol) inaccordance with the procedure of Example 235

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.6 Hz,2H), 7.50 (d, J=8.1 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.13-7.04 (m, 3H),6.95 (d, J=7.7 Hz, 1H), 4.35 (t, J=7.0 Hz, 2H), 3.94 (s, 3H), 3.21 (brs,4H), 2.73 (brs, 4H), 2.46 (t, J=7.5 Hz, 2H), 1.99-1.94 (m, 2H),1.60-1.47 (m, 4H)

Example 2.50 9-(5-(4-Phenylpiperidin-1-yl)pentyl)-9H-carbazole

226.4 mg (0.52 mmol, 83% yield) of the title compound was prepared usingthe compound of Example 1.5 (200 mg, 0.63 mmol) and 4-phenylpiperidine(153 mg, 0.95 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.7 Hz, 2H), 7.42-7.38 (m, 2H),7.32 (d, J=8.2 Hz, 2H), 7.24-7.12 (m, 7H), 4.18 (t, J=6.8 Hz, 2H), 3.10(brd, J=11.7 Hz, 2H), 2.52-2.41 (m, 3H), 2.29 (t, J=11.4 Hz, 2H),2.16-2.05 (m, 2H), 1.82-1.73 (m, 4H), 1.63-1.55 (m, 2H), 1.22 (quint,J=7.7 Hz, 2H)

Example 2.51 9-(5-(4-Benzylpiperazin-1-yl)pentyl)-9H-carbazole

248.0 mg (0.60 mmol, 95% yield) of the title compound was prepared usingthe compound of Example 1.5 (200 mg, 0.63 mmol) and benzylpiperazine(0.13 ml, 0.76 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.7 Hz, 2H), 7.41-7.37 (m, 2H),7.30 (d, J=8.2 Hz, 2H), 7.26-7.15 (m, 7H), 4.17 (t, J=7.1 Hz, 2H), 3.44(s, 2H), 2.39 (brs, 8H), 2.19 (t, J=7.7 Hz, 2H), 1.79 (quint, J=7.4 Hz,2H), 1.43 (quint, J=7.6 Hz, 2H), 1.28 (quint, J=7.6 Hz, 2H)

Example 2.52 2-(4-(5-(9H-carbazol-9-yl)pentyl)piperazin-1-yl)phenol

172.3 mg (0.42 mmol, 66% yield) of the title compound was prepared usingthe compound of Example 1.5 (200 mg, 0.63 mmol) and1-(2-hydroxyphenyl)piperazine (169 mg, 0.95 mmol) in accordance with theprocedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.7 Hz, 2H), 7.42-7.38 (m, 2H),7.31 (d, J=8.2 Hz, 2H), 7.19-7.15 (m, 2H), 7.09-7.06 (m, 1H), 7.03-6.99(m, 1H), 6.92 (dd, J=6.0 Hz, J=1.5 Hz, 1H), 6.80 (td, J=7.6 Hz, J=1.5Hz, 1H), 4.16 (t, J=7.1 Hz, 2H), 2.79 (t, J=4.7 Hz, 4H), 2.41 (brs, 4H),2.20 (t, J=7.6 Hz, 2H), 1.79 (quint, J=7.4 Hz, 2H), 1.41 (quint, J=7.5Hz, 2H), 1.32-1.24 (m, 2H)

Example 2.539-(5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl)-9H-carbazole

247.7 mg (0.58 mmol, 92% yield) of the title compound was prepared usingthe compound of Example 1.5 (200 mg, 0.63 mmol) and1-(2-methoxyphenyl)piperazine (0.13 ml, 0.76 mmol) in accordance withthe procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=7.7 Hz, 2H), 7.43-7.39 (m, 2H),7.32 (d, J=8.2 Hz, 2H), 7.20-7.16 (m, 2H), 6.95-6.84 (m, 3H), 6.77 (d,J=7.6 Hz, 1H), 4.18 (t, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.04 (brs, 4H),2.55 (brs, 4H), 2.27 (t, J=7.7 Hz, 2H), 1.81 (quint, J=7.4 Hz, 2H), 1.48(quint, J=7.6 Hz, 2H), 1.31 (quint, J=7.6 Hz, 2H)

Example 2.54 9-(4-(4-Phenylpiperidin-1-yl)butyl)-9H-carbazole

213.5 mg (0.56 mmol, 84% yield) of the title compound was prepared usingthe compound of Example 1.6 (200 mg, 0.66 mmol) and 4-phenylpiperidine(160 mg, 0.99 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.02 (d, J=7.7 Hz, 2H), 7.40-7.36 (m, 2H),7.30 (d, J=8.2 Hz, 2H), 7.23-7.09 (m, 7H), 4.14 (t, J=7.2 Hz, 2H), 2.85(brd, J=11.2 Hz, 2H), 2.36-2.29 (m, 1H), 2.21 (t, J=7.5 Hz, 2H),1.87-1.67 (m, 8H), 1.49 (quint, J=7.6 Hz, 2H)

Example 2.55 2-(4-(4-(9H-carbazol-9-yl)butyl)piperazin-1-yl)phenol

104.5 mg (0.26 mmol, 40% yield) of the title compound was prepared usingthe compound of Example 1.6 (200 mg, 0.66 mmol) and1-(2-hydroxyphenyl)piperazine (177 mg, 0.99 mmol) in accordance with theprocedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H),7.37 (d, J=8.1 Hz, 2H), 7.22-7.18 (m, 2H), 7.09 (dd, J=5.9 Hz, J=1.5 Hz,1H), 7.05-7.01 (m, 1H), 6.92 (dd, J=6.0 Hz, J=1.4 Hz, 1H), 6.81 (td,J=7.6 Hz, J=1.5 Hz, 1H) 4.25 (t, J=7.1 Hz, 2H), 2.80 (t, J=4.7 Hz, 4H),2.45 (brs, 4H), 2.31 (t, J=7.4 Hz, 2H), 1.86 (quint, J=7.4 Hz, 2H), 1.52(quint, J=7.5 Hz, 2H)

Example 2.56 9-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-9H-carbazole

256.4 mg (0.62 mmol, 94% yield) of the title compound was prepared usingthe compound of Example 1.6 (200 mg, 0.66 mmol) and1-(2-methoxyphenyl)piperazine (0.14 ml, 0.79 mmol) in accordance withthe procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.7 Hz, 2H), 7.42-7.38 (m, 2H),7.33 (d, J=8.1 Hz, 2H), 7.19-7.15 (m, 2H), 6.95-6.88 (m, 1H), 6.85 (d,J=4.0 Hz, 2H), 6.75 (d, J=7.8 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 3.74 (s,3H), 3.00 (brs, 4H), 2.50 (brs, 4H), 2.31 (t, J=7.4 Hz, 2H), 1.81(quint, J=7.4 Hz, 2H), 1.50 (quint, J=7.5 Hz, 2H)

Example 2.57 9-(3-(4-Phenylpiperidin-1-yl)propyl)-9H-carbazole

132.9 mg (0.36 mmol, 52% yield) of the title compound was prepared usingthe compound of Example 1.7 (200 mg, 0.69 mmol) and 4-benzylpiperidine(168 mg, 1.04 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.06 (dt, J=7.7 Hz, J=0.8 Hz, 2H), 7.46-7.40(m, 4H), 7.29-7.26 (m, 2H), 7.23-7.15 (m, 5H), 4.32 (t, J=6.7 Hz, 2H),2.90 (brd, J=11.5 Hz, 2H), 2.46-2.38 (m, 1H), 2.27 (t, J=6.8 Hz, 2H),1.99 (quint, J=6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.83-1.71 (m, 4H)

Example 2.58 9-(3-(4-Benzylpiperazin-1-yl)propyl)-9H-carbazole

204.6 mg (0.53 mmol, 77% yield) of the title compound was prepared usingthe compound of Example 1.7 (200 mg, 0.69 mmol) and benzylpiperazine(0.14 ml, 0.83 mmol) in accordance with the procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.04-8.02 (m, 2H), 7.41-7.36 (m, 4H),7.30-7.24 (m, 4H), 7.23-7.14 (m, 3H), 4.26 (t, J=6.7 Hz, 2H), 3.46 (s,2H), 2.39 (brd, J=41.2 Hz, 8H), 2.21 (t, J=6.8 Hz, 2H), 1.92 (quint,J=6.7 Hz, 2H)

Example 2.59 2-(4-(3-(9H-carbazol-9-yl)propyl)piperazin-1-yl)phenol

131.6 mg (0.34 mmol, 60% yield) of the title compound was prepared usingthe compound of Example 1.7 (176 mg, 0.61 mmol) and1-(2-hydroxyphenyl)piperazine (153 mg, 0.86 mmol) in accordance with theprocedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=7.7 Hz, 2H), 7.46-7.41 (m, 4H),7.24-7.15 (m, 3H), 7.08-7.03 (m, 1H), 6.94 (dd, J=6.0 Hz, J=1.4 Hz, 1H),6.85 (td, J=7.6 Hz, J=1.5 Hz, 1H), 4.36 (t, J=6.6 Hz, 2H), 2.85 (t,J=4.7 Hz, 4H), 2.47 (brs, 4H), 2.30 (t, J=6.7 Hz, 2H), 2.01 (quint,J=6.6 Hz, 2H)

Example 2.609-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-9H-carbazole

145.8 mg (0.36 mmol, 60% yield) of the title compound was prepared usingthe compound of Example 1.7 (176 mg, 0.61 mmol) and1-(2-methoxyphenyl)piperazine (0.13 ml, 0.73 mmol) in accordance withthe procedure of Example 2.35.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=7.8 Hz, 2H), 7.43-7.37 (m, 4H),7.19-7.15 (m, 2H), 6.96-6.86 (m, 3H), 6.78-6.76 (m, 1H), 4.29 (t, J=6.6Hz, 2H), 3.75 (s, 3H), 3.06 (brs, 4H), 2.50 (brs, 4H), 2.26 (t, J=6.7Hz, 2H), 1.94 (quint, J=6.6 Hz, 2H)

Formulation Examples

The inventive carbazole derivatives can be formulated into variousdosage forms according to the intended purpose. Exemplary formulationscontaining the carbazole derivatives or pharmaceutically acceptablesalts thereof as an active ingredient are provided hereinbelow. However,these formulation examples are merely illustrative and the scope of thepresent invention is not limited thereto.

Formulation Example 1 Tablets (Direct Compression)

5.0 mg of the compound prepared in Example 2.15 was sieved and mixedwith 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg ofmagnesium stearate. The mixture was compressed into tablets.

Formulation Example 2 Tablets (Wet Granulation)

5.0 mg of the compound prepared in Example 2.15 was sieved and mixedwith 16.0 mg of lactose and 4.0 mg of starch. To the mixture was addedan appropriate amount of a solution of 0.3 mg of polysorbate 80 in purewater. The resulting mixture was granulated. After drying, the granuleswere sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0mg of magnesium stearate. The mixture was compressed into tablets.

Formulation Example 3 Powders and Capsules

5.0 mg of the compound prepared in Example 2.15 was sieved and mixedwith 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg ofmagnesium stearate. The mixture was filled in hard No. 5 gelatincapsules using a proper device.

Formulation Example 4 Injectable Preparations

100 mg of the compound prepared in Example 2.15, 180 mg of mannitol, 26mg of Na₂HPO₄.12H₂O, and 2,974 mg of distilled water were mixed toproduce injectable preparations.

Experimental Example 1 Measurement of Binding Affinity for the 5-HT₇Serotonin Receptor

In this example, the human gene recombinant 5-HT₇ receptor expressed inCHO cells was used. 1 nM [³H]LSD, 5-HT₇ receptor membrane (15 μg/well),a test drug, 10 mM MgCl₂, 50 mM Tris-HCl buffer (pH 7.4) containing 0.1mM EDTA, etc. were added to a vessel until the final volume reached 0.25ml. The test drug was used at various concentrations. The mixture wascultured at 25° C. for 90 min. The culture was rapidly filtered througha Whatman GF/C glass fiber filter, which had been previously wetted with0.3% polyethyleneimine using a Brandel harvester, to quench thereaction. The reaction mixture was washed with cold 50 mM Tris-HClbuffer. The filter was covered with MeltiLex, sealed in a sample bag,and dried in an oven. Counting was performed using MicroBeta (Wallac)and nonspecific binding was measured in the presence of 0.5 mianserin.The K value of the test drug was obtained from nonlinear regressionanalysis (GraphPad Prism Program, San Diego, USA) of isotherms obtainedby repeatedly performing the experiment on the drug at 10-11 stageconcentrations in two test tubes (each twice).

The % inhibition values of the inventive compounds having different Ystructures at a concentration of 10 μM against the 5-HT₇ serotoninreceptor were measured. Further, the binding affinity (K_(i)) values ofthe inventive compounds having different Y structures at a concentrationof 10 μM for the 5-HT₇ serotonin receptor were measured. The results areshown in Tables 1 to 3.

TABLE 1 Y 5-HT₇ 5-HT_(1E) 5-HT_(2C) Example No. (structure) % inhibitionKi (nM) % inhibition Ki (nM) % inhibition Ki (nM) Example 2.1 Example2.17 Example 2.35

82.8 50.0 70.7 680 1281  511 51.3 73.9 55.7 — — — 87.4 — 59.4 207 — —Example 2.2 Example 2.18 Example 2.36

92.0 83.1 64.0 604 513 1980  10.2 −22.5  −13.2  — — — 54.6 32.6 — 1315 — — Example 2.3 Example 2.19 Example 2.37

74.0 57.4 66.9 1051  2157  1546  13.9 16.3 21.1 — — — 76.7 45.0 — 764 —— Example 2.7 Example 2.23 Example 2.41

86.0 77.0 71.3 616 949 952  1.8 −11.7   2.7 — — — 77.2 55.0 — 411 1088 — Example 2.4 Example 2.20 Example 2.38

94.2 80.2 82.9 364 592 597 −11.6  −19.3  −9.4 — — — 78.5 44.4 — 878 — —Example 2.5 Example 2.21 Example 2.39

84.6 69.4 75.6 550 883 909 −15.3  −6.0  1.5 — — — 86.6 50.0 — 486 — —Example 2.6 Example 2.22 Example 2.40

77.2 67.6 57.7 833 1398  1598  −21.9  −10.5  −7.3 — — — 80.6 52.1 — 454852 —

Referring to the results in Table 1, the compounds wherein Y is NR₁R₂(R₁ and R₂ are alkyl groups that are not bonded to each other and cannotform a ring) showed good inhibitory effects on both 5-HT₇ and 5-HT_(2C),and particularly, they showed very good inhibitory effects on 5-HT_(1E)compared to the other carbazole compounds.

Meanwhile, the compounds wherein Y is NR₁R₂ and (R₁ and R₂ are notbonded to each other and cannot form a ring and either R₁ or R₂ is abenzyl group) and the compounds wherein Y is NR₁R₂ (R₁ and R₂ are bondedto each other to form a ring) showed no inhibitory effects on 5-HT_(1E)but showed good inhibitory effects on 5-HT₇ and 5-HT_(2C). Particularly,the compounds in which the alkyl chain between X and Y consists of 5carbon atoms had significantly high % inhibition values against5-HT_(2C).

TABLE 2 Y 5-HT₇ 5-HT_(2C) 5-HT₆ Example No. (structure) % inhibition Ki(nM) % inhibition Ki (nM) % inhibition Ki (nM) Example 2.9 Example 2.25Example 2.43 Example 2.50 Example 2.54 Example 2.57

99.8 96.0 89.9 94.1 94.4 91.1 157 153 212 178 205 353 55.3 53.2 — — —758 905 — — — 92.2 67.0 94.9 96.1 55.5 32.9 373 1496  169 123 1429  —Example 2.10 Example 2.26 Example 2.44

102.9  97.4 86.8 252 312 232 70.4 43.1 — 683 — — 91.9 93.4 97.8 354 302142

Referring to the results in Table 2, the compounds wherein Y is asubstituted piperidinyl group were found to have very high % inhibitionvalues of 89.9 to 103.0 against 5-HT₇, together with good inhibitoryeffects on 5-HT_(2C) and 5-HT₆. Meanwhile, the compounds had very low %inhibition values of −12.4 to 13.5 against 5-HT_(1E). The % inhibitionvalues of the compounds against 5-HT₆ were greatly affected by thenumber (n) of carbon atoms of the alkyl chain between X and Y.Specifically, the compounds in which the alkyl chain consists of 5carbon atoms had the highest % inhibition values. The % inhibition valuedecreased significantly with decreasing length of the alkyl chain. Thecompounds wherein X is CO showed higher % inhibition values against5-HT₇, whereas the compounds wherein X is CH₂ showed higher % inhibitionvalues against 5-HT₆.

TABLE 3 5-HT₇ 5-HT_(1A) 5-HT_(2C) 5-HT₆ Example No. Y (structure) %inhibiton Ki (nM) % inhibition % inhibition % inhibition Example 2.12Example 2.28 Example 2.46

50.0 40.4 49.4 1910  — —  5.5  15.9  19.3 82.5 — — 77.6 78.4 82.2Example 2.11 Example 2.27 Example 2.45

72.1 64.6 63.1 2336  1072  1485   51.8  25.4  6.2 51.3  6.6 — 24.5 13.835.0 Example 2.13 Example 2.29 Example 2.32 Exmaple 2.47 Example 2.51Example 2.58

94.8 92.0 90.8 86.0 86.8 88.7 127 282 404 602 233 404 76.8 66.5 69.562.0 74.9 64.9 72.3 38.0 — — — — 57.9 57.4 14.7 77.5 65.1 15.1 Example2.14

94.1  73 80.5 63.7 81.3 Example 2.15 Example 2.30 Example 2.33 Example2.48 Example 2.52 Example 2.55 Example 2.59

100.3  98.7 97.0 90.5 94.4 95.8 94.7  38  86  50  89  31  55  96 94.2102.2  100.9  105.2  102.6  103.2  104.7  73.5 — — — — — — 85.3 62.616.1 96.9 95.5 77.8 21.7 Example 2.16 Example 2.31 Example 2.34 Example2.49 Example 2.53 Example 2.56 Example 2.60

102.0  99.6 97.7 85.7 91.5 92.5 90.7  74  30  33 145  65  64 155 108.0 103.2  103.6  104.7  101.1  104.5  102.7  55.8 62.6 74.2 — — — — 30.744.4 51.5 85.1 75.5 56.3 12.2

Referring to the results in Table 3, the compounds wherein Y apiperazinyl groups whose nitrogen atom is substituted with alkyl (R₅)showed good inhibitory effects on 5-HT_(2C) and 5-HT₆ together with5-HT₇. On the other hand, the compounds wherein R₅ is an aryl group, aheteroaryl group or benzyl showed good inhibitory effects on 5-HT_(1A)as well as 5-HT_(2C) and 5-HT₆, together with 5-HT₇. Particularly, thecompounds wherein R₅ is an aryl group showed excellent inhibitoryeffects on 5-HT_(1A). On the other hand, the compounds in which thealkyl chain consists of 5 carbon atoms had the highest % inhibitionvalues against 5-HT₆, as in the results in Table 2. The % inhibitionvalue decreased significantly with decreasing length of the alkyl chain.The compounds wherein X is CO showed higher % inhibition values against5-HT₇, whereas the compounds wherein X is CH₂ showed higher % inhibitionvalues against 5-HT₆.

Referring to the results in Tables 1-3, when Y has a structure withinthe range defined above and X is CH₂ irrespective of the structure of Y,the compounds wherein n is 5 showed lower % inhibition values againstthe 5-HT₇ receptor compared to the compounds wherein n is from 2 to 4.The compounds wherein n is 5 have a carbazole-(CH₂)₅—Y structure inwhich X (CH₂) is connected to the alkyl chain ((CH₂)₅). This structureis estimated to lower the % inhibition values of the compounds wherein nis 5 against the 5-HT₇ receptor.

In order to investigate the inhibitory effect of the length of the alkylchain between the carbazole moiety and the tertiary amine (Y) on the5-HT₇ receptor when n is greater than 5, the compounds wherein n is 6and the compounds wherein n is 7 were prepared (Comparative Examples1-6).

The compound of Comparative Example 1 wherein Y is 4-phenylpiperidyl, Xis CO, and n is 6 and the compound of Comparative Example 2 wherein Y is4-phenylpiperidyl, X is CO, and n is 7 were measured to have %inhibition values of 47.5 and 32.8 against the 5-HT₇ receptor,respectively, which were lower than those of the compounds of Examples2.9 and 2.25 shown in Table 2. The compound of Comparative Example 3wherein Y is 4-phenylpiperidyl, X is CH₂, and n is 6 was measured tohave a % inhibition value of 42.7 against the 5-HT₇ receptor, which waslower than that of the compound of Example 2.43 shown in Table 2.

The compound of Comparative Example 4 wherein Y is2-methoxyphenylpiperazinyl, X is CO, n is 6, the compound of ComparativeExample 5 wherein Y is 2-methoxyphenylpiperazinyl, X is CH₂, and n is 6,and the compound of Comparative Example 6 wherein Y is2-methoxyphenylpiperazinyl, X is CH₂, and n is 7 were measured to have %inhibition values of 44.5, 42.7, and 19.7 against the 5-HT₇ receptor,respectively, which were lower in efficacy than those of the inventivecompounds wherein Y is 2-methoxyphenylpiperazinyl shown in Table 3.

From these results, it can be seen that the compounds wherein n is from2 to 5 can effectively act on the 5-HT₇ receptor. Particularly, thecompounds wherein n is 7 or greater had considerably low % inhibitionvalues, making it substantially difficult to apply the compounds asantagonists against the 5-HT₇ receptor, and therefore, they are notexpected to be useful for the treatment or prevention of central nervoussystem diseases, such as depression, migraine, anxiety, pain,inflammatory pain, neuropathic pain, body temperature dysregulation,circadian rhythm dysregulation, sleep disturbance, and smoothmuscle-related diseases.

Experimental Example 2 Antagonism Against Migraine

It is known that inflammatory proteins leaked from meningeal vessels by5-HT are implicated in causing migraine. The amount of the proteinsleaked in the presence of the compound of Example 2.10 was measured andthe preventive effect of the compound on migraine was assessed by apartial modification of the method described in the literature [RachelA. Spokes, Vicki C. Middlefell, European Journal of Pharmacology (1995)281, 75-79]. SB-269970, which is known as a 5-HT₇ receptor antagonizingcompound (J. Med. Chem. (2000) 43, 342-345), was used as a comparativecompound. A negative control free of 5-HT₇ was prepared. Thefluorescence intensity of the negative control was defined as areference value. As a positive control, physiological saline was addedinstead of the compound of Example 2-10.

Rats (350-450 g) were administered urethane (1.5 g/kg)intraperitoneally. 50 mg/kg of a fluorescent protein (FITC-BSA) wasadministered intravenously through a cannula introduced into thesaphenous vein, and 1 μM 5-HT₇ was administered intravenously. SB-269970and the compound of Example 2.10 were administered intraperitoneally.The cerebral lobes were separated and the meninges were drawn from eachrat. The meninges were allowed to stand at 37° C. for 16 h in thepresence of physiological saline at pH 11, followed by centrifugation.The supernatant was plated on plates. The fluorescence intensity wasmeasured using a fluorescence leader (excitation wavelength 485 nm,absorption wavelength 530 nm) and the meninges were weighed. Thefluorescence intensity per mg of the meningeal proteins was calculated.

The 5-HT₇ receptor antagonizing compound SB-269970 reduced the amount ofthe proteins leaked by 10 mg/kg. Even when SB-269970 was administered atan increased dose of 30 mg/kg, the amount of the proteins leaked was notlowered down to the reference value. In contrast, when the compound ofExample 2.10 was administered at a dose of 3 mg/kg, the amount of theproteins leaked was effectively suppressed to a level close to thereference value. The results are shown in FIG. 1.

When each of the compounds of Examples 2.4, 2.9, 2.14, 2.15, 2.31, and2.55 was administered in an amount of 5 mg/kg to 20 mg/kg, the proteinleakage was suppressed to a level close to the reference value.

These results lead to the conclusion that the inventive compounds caneffectively inhibit migraine.

What is claimed is:
 1. A carbazole derivative represented by Formula 1:

wherein X is CH₂ or C(O), Y is selected from NR₁R₂, piperidinyl groupssubstituted with R₃ and R₄, piperazinyl groups in which the nitrogenatom is substituted with R₅, and morpholinyl groups, n is an integerfrom 2 to 5, R₁ and R₂ are identical or different and are eachindependently selected from C₁-C₆ alkyl, phenyl, and benzyl, with theproviso that R₁ and R₂ are optionally bonded together to form a ring, R₃and R₄ are identical or different and are each independently selectedfrom hydrogen, C₁-C₆ alkyl, phenyl, and benzyl, and R₅ is selected fromC₁-C₆ alkyl, C₁-C₄ alkylcarbonyl, phenyl substituted with C₁-C₄alkyloxy, hydroxyphenyl, benzyl, and benzoisoxazol-3-yl; or apharmaceutically acceptable salt thereof.
 2. The carbazole derivative orpharmaceutically acceptable salt thereof according to claim 1, whereinthe carbazole derivative represented by Formula 1 is selected fromcompounds represented by Formulae 2 to 5:

wherein X is CH₂ or C(O), n is an integer from 2 to 5, and R₁ and R₂ areidentical or different and are each independently selected from C₁-C₆alkyl, phenyl, and benzyl, with the proviso that R₁ and R₂ areoptionally bonded together to form a ring;

wherein X, n, and R₂ are as defined in Formula 2, and R₃ is selectedfrom hydrogen, C₁-C₆ alkyl, phenyl, and benzyl;

wherein X and n are as defined in Formula 2, and R₅ is selected fromC₁-C₆ alkyl, C₁-C₄ alkylcarbonyl, phenyl substituted with C₁-C₄alkyloxy, hydroxyphenyl, benzyl, and benzoisoxazol-3-yl; and

wherein X and n are as defined in Formula
 2. 3. The carbazole derivativeor pharmaceutically acceptable salt thereof according to claim 1,wherein Y is selected from methylbutylaminyl, methylbenzylaminyl,pyrrolidinyl, azepanyl, morpholinyl, 4-methylpiperidinyl,3-methylpiperidinyl, 3,5-dimethylpiperidinyl, 4-phenylpiperidinyl,4-benzylpiperidinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl,4-(2-methoxyphenyl)piperazinyl, 4-(2-hydroxyphenyl)piperazinyl,4-benzylpiperazinyl, and 4-(benzoisoxazol-3-yl)piperazinyl.
 4. Thecarbazole derivative or pharmaceutically acceptable salt thereofaccording to claim 1, wherein the carbazole derivative represented byFormula 1 is selected from:6-(butyl(methyl)amino)-1-(9H-carbazol-9-yl)hexan-1-one;6-(benzyl(methyl)amino)-1-(9H-carbazol-9-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(pyrrolidin-1-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(4-methylpiperidin-1-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(3-methylpiperidin-1-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(3,5-dimethylpiperidin-1-yl)hexan-1-one;6-(azepan-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-morpholinohexan-1-one;1-(9H-carbazol-9-yl)-6-(4-phenylpiperidin-1-yl)hexan-1-one;6-(4-benzylpiperidin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one;6-(4-acetylpiperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(4-methylpiperazin-1-yl)hexan-1-one;6-(4-benzylpiperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one;6-(4-benzo[d]isoxazol-3-yl)piperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(4-(2-hydroxyphenyl)piperazin-1-yl)hexan-1-one;1-(9H-carbazol-9-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)hexan-1-one;5-(butyl(methyl)amino)-1-(9H-carbazol-9-yl)pentan-1-one;5-(benzyl(methyl)amino)-1-(9H-carbazol-9-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(pyrrolidin-1-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(4-methylpiperidin-1-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(3-methylpiperidin-1-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(3,5-dimethylpiperidin-1-yl)pentan-1-one;5-(azepan-1-yl)-1-(9H-carbazol-9-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-morpholinopentan-1-one;1-(9H-carbazol-9-yl)-5-(4-phenylpiperidin-1-yl)pentan-1-one;5-(4-benzylpiperidin-1-yl)-1-(9H-carbazol-9-yl)pentan-1-one;5-(4-acetylpiperazin-1-yl)-1-(9H-carbazol-9-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(4-methylpiperazin-1-yl)pentan-1-one;5-(4-benzylpiperazinyl)-1-(9H-carbazol-9-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(4-(2-hydroxyphenyl)piperazin-1-yl)pentan-1-one;1-(9H-carbazol-9-yl)-5-(4-(2-methoxyphenyl)piperazin-1-yl)pentan-1-one;4-(4-benzylpiperazin-1-yl)-1-(9H-carbazol-9-yl)butan-1-one;1-(9H-carbazol-9-yl)-4-(4-(2-hydroxyphenyl)piperazin-1-yl)butan-1-one;1-(9H-carbazol-9-yl)-4-(4-(2-methoxyphenyl)piperazin-1-yl)butan-1-one;N-butyl-6-(9H-carbazol-9-yl)-N-methylhexane-1-amine;N-benzyl-6-(9H-carbazol-9-yl)-N-methylhexane-1-amine;9-(6-(pyrrolidin-1-yl)hexyl)-9H-carbazole;9-(6-(4-methylpiperidin-1-yl)hexyl)-9H-carbazole;9-(6-(3-methylpiperidin-1-yl)hexyl)-9H-carbazole;9-(6-(3,5-dimethylpiperidin-1-yl)hexyl)-9H-carbazole;9-(6-(azepan-1-yl)hexyl)-9H-carbazole;4-(6-(9H-carbazol-9-yl)hexyl)morpholine;9-(6-(4-phenylpiperidin-1-yl)hexyl)-9H-carbazole;9-(6-(4-benzylpiperidin-1-yl)hexyl)-9H-carbazole;1-(4-(6-(9H-carbazol-9-yl)hexyl)piperazin-1-yl)ethanone;9-(6-(4-methylpiperazin-1-yl)hexyl)-9H-carbazole;9-(6-(4-benzylpiperazin-1-yl)hexyl)-9H-carbazole;2-(4-(6-(9H-carbazol-9-yl)hexyl)piperazin-1-yl)phenol;9-(6-(4-(2-methoxyphenyl)piperazin-1-yl)hexyl)-9H-carbazole;9-(5-(4-phenylpiperidin-1-yl)pentyl)-9H-carbazole;9-(5-(4-benzylpiperazin-1-yl)pentyl)-9H-carbazole;2-(4-(5-(9H-carbazol-9-yl)pentyl)piperazin-1-yl)phenol;9-(5-(4-(2-methoxyphenyl)piperazin-1-yl)pentyl)-9H-carbazole;9-(4-(4-phenylpiperidin-1-yl)butyl)-9H-carbazole;2-(4-(4-(9H-carbazol-9-yl)butyl)piperazin-1-yl)phenol;9-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-9H-carbazole;9-(3-(4-phenylpiperidin-1-yl)propyl)-9H-carbazole;9-(3-(4-benzylpiperazin-1-yl)propyl)-9H-carbazole;2-(4-(3-(9H-carbazol-9-yl)propyl)piperazin-1-yl)phenol; and9-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-9H-carbazole.
 5. Amethod for preparing a carbazole derivative represented by Formula 1:

wherein X is CH₂ or C(O), Y is selected from NR₁R₂, piperidinyl groupssubstituted with R₃ and R₄, piperazinyl groups in which the nitrogenatom is substituted with R₅, and morpholinyl groups, n is an integerfrom 2 to 5, R₁ and R₂ are identical or different and are eachindependently selected from C₁-C₆ alkyl, phenyl, and benzyl, with theproviso that R₁ and R₂ are optionally bonded together to form a ring, R₃and R₄ are identical or different and are each independently selectedfrom hydrogen, C₁-C₆ alkyl, phenyl, and benzyl, and R₅ is selected fromC₁-C₆ alkyl, C₁-C₄ alkylcarbonyl, phenyl substituted with C₁-C₄alkyloxy, hydroxyphenyl, benzyl, and benzoisoxazol-3-yl, the methodcomprising reacting a compound represented by Formula 6:

wherein X and n are as defined in Formula 1, with a compound representedby Formula 7:Y—H  (7) wherein Y is as defined in Formula 1, in an organic solvent. 6.The method according to claim 5, wherein the organic solvent is selectedfrom the group consisting of acetonitrile, dichloromethane,dichloroethane, tetrahydrofuran, lower alcohol, N,N-dimethylformamide,dimethyl sulfoxide, ethyl acetate, dioxane, chloroform, benzene, andtoluene.
 7. The method according to claim 5, wherein the reaction iscarried out under reflux at 25 to 200° C. for 3 to 24 hours.
 8. Themethod according to claim 7, wherein Y is selected frommethylbutylaminyl, methylbenzylaminyl, pyrrolidinyl, azepanyl,morpholinyl, 4-methylpiperidinyl, 3-methylpiperidinyl,3,5-dimethylpiperidinyl, 4-phenylpiperidinyl, 4-benzylpiperidinyl,4-methylpiperazinyl, 4-acetylpiperazinyl,4-(2-methoxyphenyl)piperazinyl, 4-(2-hydroxyphenyl)piperazinyl,4-benzylpiperazinyl, and 4-(benzoisoxazol-3-yl)piperazinyl.
 9. Themethod according to claim 5, wherein the compound of Formula 6 isprepared by reacting carbazole with a compound of Formula 8:

wherein X is CH₂ or C(O), and n is an integer from 2 to 5, in an organicsolvent.
 10. A pharmaceutical composition for preventing and treating acentral nervous system disease, comprising a carbazole derivativerepresented by Formula 1:

wherein X is CH₂ or C(O), Y is selected from NR₁R₂, piperidinyl groupssubstituted with R₃ and R₄, piperazinyl groups in which the nitrogenatom is substituted with R₅, and morpholinyl groups, n is an integerfrom 2 to 5, R₁ and R₂ are identical or different and are eachindependently selected from C₁-C₆ alkyl, phenyl, and benzyl, with theproviso that R₁ and R₂ are optionally bonded together to form a ring, R₃and R₄ are identical or different and are each independently selectedfrom hydrogen, C₁-C₆ alkyl, phenyl, and benzyl, and R₅ is selected fromC₁-C₆ alkyl, C₁-C₄ alkylcarbonyl, phenyl substituted with C₁-C₄alkyloxy, hydroxyphenyl, benzyl, and benzoisoxazol-3-yl, or apharmaceutically acceptable salt thereof as an active ingredient. 11.The pharmaceutical composition according to claim 10, wherein thecentral nervous system disease is selected from the group consisting ofdepression, migraine, anxiety, pain, inflammatory pain, neuropathicpain, body temperature dysregulation, circadian rhythm dysregulation,sleep disturbance, smooth muscle-related diseases, and combinationsthereof.
 12. The pharmaceutical composition according to claim 10,wherein the carbazole derivative represented by Formula 1 is selectedfrom compounds represented by Formulae 2 to 5:

wherein X is CH₂ or C(O), n is an integer from 2 to 5, and R₁ and R₂ areidentical or different and are each independently selected from C₁-C₆alkyl, phenyl, and benzyl, with the proviso that R₁ and R₂ areoptionally bonded together to form a ring;

wherein X, n, and R₂ are as defined in Formula 2, and R₃ is selectedfrom hydrogen, C₁-C₆ alkyl, phenyl, and benzyl;

wherein X and n are as defined in Formula 2, and R₅ is selected fromC₁-C₆ alkyl, C₁-C₄ alkylcarbonyl, phenyl substituted with C₁-C₄alkyloxy, hydroxyphenyl, benzyl, and benzoisoxazol-3-yl; and

wherein X and n are as defined in Formula 2.